Polymeric Adhesive Matrix with Salified Carboxylic Groups for Transdermal Use

ABSTRACT

Polymeric matrices for the controlled release of medicaments for the topical transdermal use comprising copolymers of acrylic and/or methacrylic acid or esters thereof having a Tg lower than 0.degree. C., whose free carboxy groups are salified with compatible organic or inorganic bases. The matrices of the invention allow to prepare therapeutical systems for the controlled-release of active principles through the transdermal route, thus solving stability, solubility and/or bioavailability problems of the active ingredient within the matrix.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of and claims the benefit from U.S.application Ser. No. 11/659,379 filed on Aug. 4, 2008, which claimspriority to PCT NO: PCT/EP2005/007293 filed Jul. 6, 2005, which claimspriority to Italian patent application MI2004A001628, filed Aug. 6,2004, all of which are incorporated by reference in their entirety forall purposes as if fully set forth herein.

The present invention relates to a polymeric matrix for thecontrolled-release of medicaments for the topical transdermal use, whichmatrix improves the solubility and the stability of the activeingredient.

TECHNOLOGICAL BACKGROUND

Controlled-release therapeutical systems (based on a matrix) for thetransdermal administration are prepared by incorporation of an activeingredient (active principle) in a polymeric matrix, which acts both asadhesive and “container” for the medicament.

For this reason, a polymeric matrix must satisfy a series of specificrequirements:

-   -   ability to dissolve the active principle at the desired        concentrations;    -   absence of chemical interactions with the active principle, so        as to avoid degradation or alteration;    -   ability to allow the diffusion of the active principle towards        the corneous layer;    -   absence of irritation or erythema at the application site;    -   ability to ensure adhesion of the system to the skin during the        whole treatment period.

The matrices are made from solutions of adhesive polymers also referredto as “pressure sensitive adhesives”.

The most commonly used polymers are of acrylic type and are commerciallyavailable in the form of powders, granules, aqueous or solventsolutions.

In general, the polymers used for pharmaceutical formulations belong totwo classes, those with a glass transition temperature (Tg) higher thanroom temperature (or use temperature) and those with a Tg lower thanroom temperature. The former need plasticizers to be used in theformulation of transdermal patches, while the latter can be used assuch, since they already have a soft consistency. For this reason,polymers with a Tg<room T are preferred, even if, due to theirproperties, they are commercialised dissolved in organic solvents.

Many of these polymers are copolymers of acrylic or methacrylic acidand/or esters thereof, therefore the polymer chains contain acidicfunctions which can interact with the active principle causing oxidationand/or degradation of the active principle.

It has now been found that matrix-based therapeutical systems for thecontrolled release of medicaments can be prepared by suitably salifyingthe free carboxy groups of the polymer chains of macromolecules mixtureshaving a lower Tg.

DISCLOSURE OF THE INVENTION

The invention relates to a polymeric matrix for the controlled releaseof medicaments for the topical transdermal use, which matrix comprisescopolymers of acrylic or methacrylic acid and/or esters thereof having aTg lower than 0° C. and wherein the free carboxy groups are salifiedwith compatible organic or inorganic bases.

The copolymers that can be used according to the invention consist oftwo or more monomers in various percentages.

Examples of said monomers comprise:

-   -   acrylic acid    -   butyl acrylate    -   2-ethylhexyl acrylate    -   glycidyl methacrylate    -   2-hydroxyethyl acrylate    -   methyl acrylate    -   vinyl acetate    -   t-octylacrylamide

Examples of copolymers according to the invention comprisepoly(2-ethyl-hexyl acrylate-co-acrylic acid), poly(2-hydroxy-ethylacrylate-co-acrylic acid-co-methyl-acrylates), poly(2-ethyl-hexylacrylate-co-acrylic acid-co-methylacrylate), poly(2-ethyl-hexylacrylate-co-acrylic acid-co-butilacrylate-co-vinyl acetate).

These copolymers are commercially available with the following tradenames: Duro-tak® (National and Starch), MG-0607® (Dow Corning), Gelva®(UCB chemicals), Luvimer® (BASF).

These acrylic or methacrylic copolymers have a percentage of freecarboxy groups of 0.1-15%, preferably 1-10%. Since they are nothot-extrudable, they are commercialised dissolved in organic solvents.

The bases with which the carboxy groups are salified can be eitherinorganic, for example alkali, alkaline-earth or transition metalshydroxides, carbonates or bicarbonates, or organic, for example ammonia,ammonium methyl acrylates copolymers, ethylenediamine, lysine.

The matrices of the invention further comprise from 0.1 to 20% by weightof water, preferably 1 to 5%.

The invention allows to formulate any active ingredient havingtherapeutical, dermatological or cosmetic activity when administeredthrough topical and/or transdermal route.

Examples of medicaments which can be advantageously formulated accordingto the invention comprise: non steroidal antiinflammatory agents,corticosteroids, local anaesthetics, alpha-adrenergic agonists,analgesics, antimigraine drugs, anti-allergics, antihistaminics,antimicrobials, antiemetics, anticholinergics, bronchodilators,antivirals, myorelaxants, cholinergic agents, central nervous systemstimulators, cardioactive agents, beta-adrenergic agonists, hormones,anxiolytics, antidepressants, antipsychotics, opioid antagonists,coronary dilators.

Particularly preferred are non steroidal antiinflammatories such asDiclofenac, Fenoprofen, Flurbiprofen, Ibuprofen, Ibuproxam, Indoprofen,Ketoprofen, Ketorolac, Naproxen, Oxametacine, Oxyphenbutazone,Piroxicam, Suprofen, Celecoxib and other COX-2 selective inhibitors andthe like.

The matrices of the invention are particularly suitable as adhesivelayers in transdermal patches.

A further object of the invention is a process for the preparation oftransdermal matrices which comprises the treatment of a copolymer havinga Tg lower than 0° C. and free carboxy groups suspended in an organicsolvent with an aqueous solution of organic or inorganic bases instoichiometric amounts in respect of the carboxylic groups, followed byaddition of the active ingredient and any other excipients.

The matrices of the invention allow to improve the solubility, thestability and the diffusion of the active principle from the matrix.

DETAILED DISCLOSURE OF THE INVENTION

The polymeric matrix in the final formulation can be present in anamount ranging from 20 to 95%, preferably from 50 to 90%, based on thedry weight of the final composition.

The acidic groups are neutralized with stoichiometric amounts ofinorganic (alkali and transition metal hydroxides, e.g. sodiumhydroxide, potassium hydroxide) or organic (e.g. ammonia, ammoniummethyl acrylate copolymers, ethylenediamine, lysine) bases in thepresence of a suitable amount of demineralised water to promoteion-exchange between the acidic groups of the polymeric structure andthe basic counter-ion in a solvent system.

Water is used in an amount that forms the solvatation sphere of the freeions without destabilizing the solvent system, so as to preventprecipitation of the polymer. The polymeric matrix, at firstsolvent-based, is transformed according to the invention into asolvent/water-based mixture. The amount of water ranges from 0.1 to 20%,preferably from 1 to 5% based on the wet weight of the adhesive mixture.

In this way the acidic functions are neutralised and interactions withthe active principle are avoided.

The active principle dissolves completely at high concentrations in thissystem through synergistic interaction of the polymeric matrix, thesolvent and the ion exchanges promoted by water protons. The amount ofactive principle incorporated in the system varies according to thenature of the active principle and the desired therapeutical effect.

Usually, the amount of active principle ranges from 0.1 to 50%,preferably from 0.1 to 30% based on the dry weight of the finalcomposition. After drying, the polymeric matrix that contains the activeprinciple forms a controlled-release therapeutical system for thetopical use. This matrix promotes the diffusion of the active principle,as the salification of the acidic groups in the polymeric chains makesthe matrix structure more hydrophilic.

The formulation can contain one or more excipients having differentfunctions, for example skin-emollients, percutaneous permeationenhancers, preservatives and the like. The amount of each excipientvaries within broad ranges, for example from 0.01 to 30%, and accordingto their action. Preservatives are usually comprised in the finalformulation in amounts of 0.01-2%, whereas emollients are comprised inthe final formulation in amounts of 5-20%.

The invention is illustrated in greater detail in the followingexamples.

EXAMPLE 1

1 kg of Durotak® 87-2852 (poly(2-ethyl hexyl acrylate-co-acrylicacid-co-methyl acrylate)), having a solid content of 33.5% w/w, is addedunder mechanical stirring with 62 g of a 32% w/w potassium hydroxideaqueous solution; the mixture becomes more viscous and is left undermoderate stirring for 30 min.

Thereafter, 90 g of Diclofenac are added, and stirring is continueduntil complete dissolution.

For the preparation of the matrix layer, the mixture is spread on a filmof silicon polyester and the solvents are evaporated off in a staticdrier, heating at 60° C. for 20 min. The spread matrix has a dry weightof about 50 g/m². After coupling to a polyethylene film, the patch isformed with a suitable punch.

EXAMPLE 2

1 kg of Durotak® 87-2051 (poly(2-ethyl-hexyl acrylate-co-acrylicacid-co-butyl acrylate-co-vinyl acetate)), having a solid content of 51%w/w, is added under mechanical stirring with 64 g of a 32% w/w potassiumhydroxide aqueous solution; the mixture becomes more viscous and is leftunder moderate stirring for 30 min.

Thereafter, 90 g of Ketoprofen are added, and stirring is continueduntil complete dissolution.

For the preparation of the matrix layer, the mixture is spread on a filmof silicon polyester and the solvents are evaporated off in a staticdrier, heating at 60° C. for 20 min. The spread matrix has a dry weightof about 60 g/m². After coupling to a polyethylene film, the patch isformed with a suitable punch.

EXAMPLE 3

1 kg of Durotak® 87-2852, having a content solid of 33.5% w/w, is addedunder mechanical stirring with 300 g of a 30% w/w Eudragit E100water/solvent-based solution; the mixture becomes more viscous and isleft under moderate stirring for 30 min.

Thereafter, 100 g of Diclofenac are added, and stirring is continueduntil complete dissolution.

For the preparation of the matrix layer, the mixture is spread on a filmof silicon polyester and the solvents are evaporated off in a staticdrier, heating at 60° C. for 20 min. The spread matrix has a dry weightof about 60 g/m². After coupling to a polyethylene film, the patch isformed with a suitable punch.

1. A polymeric matrix for the controlled release of medicaments for thetopical transdermal use comprising copolymers of acrylic or methacrylicacid and/or esters thereof having a Tg lower than 0° C., wherein thefree carboxy groups are salified with stoichiometric amounts ofcompatible organic bases, the organic bases comprising at least one ofammonia, ammonium methyl-acrylate copolymers, ethylenediamine, andlysine.
 2. A matrix as claimed in claim 1 wherein the copolymers areselected from poly(2-ethyl-hexyl acrylate-co-acrylic acid),poly(2-hydroxy ethylacrylate-co-acrylic acid-co-methyl acrylates),poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-methyl acrylates),poly(2-ethyl-hexyl acrylate-co-acrylic acid-co-butyl acrylate-co-vinylacetate).
 3. A matrix as claimed in claim 1 wherein the acrylic ormethacrylic copolymers have a percentage of free carboxy groups rangingfrom 0.1 to 15%.
 4. A matrix as claimed in claim 3 wherein the acrylicor methacrylic copolymers have a percentage of free carboxy groupsranging from 1 to 10%.
 5. A matrix as claimed in claim 1 comprising 0.1to 20% by weight of water.
 6. A matrix as claimed in claim 5 comprising1 to 5% by weight of water.
 7. A matrix as claimed in claim 1 asadhesive layer in a transdermal patch.
 8. A process for the preparationof the matrices of claim 1 which comprises the treatment of a copolymerhaving a Tg lower than 0° C. and free carboxylic groups suspended in anorganic solvent with an aqueous solution of organic bases instoichiometric amounts in respect of the carboxylic groups, followed byaddition of the active ingredient and any other excipients.
 9. A matrixas claimed in claim 1, further comprising a medicament selected from thegroup consisting of non-steroidal anti-inflammatory agents,corticosteroids, local anesthetics, alpha-adrenergic agonists,analgesics, antimigraine drugs, anti-allergics, antihistaminics,antimicrobials, antiemetics, anticholinergics, bronchodilators,antivirals, myorelaxants, cholinergic agents, central nervous systemstimulators, cardioactive agents, beta-adrenergic agonists, hormones,anxiolytics, antidepressants, antipsychotics, opioid antagonists, andcoronary dilators.
 10. A matrix as claimed in claim 10, wherein thenon-steroidal anti-inflammatory is selected from the group consisting ofdiclofenac, fenoprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen,ketoprofen, ketorolac, naproxen, oxametacine, oxyphenbutazone,piroxicam, suprofen, and celecoxib.
 11. A polymeric matrix for thecontrolled release of a medicament for topical or transdermal use, thematrix comprising: copolymers of at least one of acrylic acid,methacrylic acid, and esters thereof, the copolymers having a Tg lowerthan 0° C.; and stoichiometric amounts of compatible organic basessufficient to salify the free carboxy groups of the copolymers, theorganic bases comprising at least one of ammonia, ammoniummethyl-acrylate copolymers, ethylenediamine, and lysine.
 12. A matrix asclaimed in claim 11 wherein the copolymers are selected frompoly(2-ethyl-hexyl acrylate-co-acrylic acid), poly(2-hydroxyethylacrylate-co-acrylic acid-co-methyl acrylates), poly(2-ethyl-hexylacrylate-co-acrylic acid-co-methyl acrylates), poly(2-ethyl-hexylacrylate-co-acrylic acid-co-butyl acrylate-co-vinyl acetate).
 13. Amatrix as claimed in claim 11 wherein the acrylic or methacryliccopolymers have a percentage of free carboxy groups ranging from 0.1 to15%.
 14. A matrix as claimed in claim 13 wherein the acrylic ormethacrylic copolymers have a percentage of free carboxy groups rangingfrom 1 to 10%.
 15. A matrix as claimed in claim 11 comprising 0.1 to 20%by weight of water.
 16. A matrix as claimed in claim 15 comprising 1 to5% by weight of water.
 17. An adhesive layer in a transdermal patchcomprising the matrix as claimed in claim
 11. 18. A process for thepreparation of the matrices of claim 11 which comprises the treatment ofa copolymer having a Tg lower than 0° C. and free carboxylic groupssuspended in an organic solvent with an aqueous solution of organicbases in stoichiometric amounts in respect of the carboxylic groups,followed by addition of the active ingredient and any other excipients.19. A matrix as claimed in claim 18, further comprising a medicamentselected from the group consisting of non-steroidal anti-inflammatoryagents, corticosteroids, local anesthetics, alpha-adrenergic agonists,analgesics, antimigraine drugs, anti-allergics, antihistaminics,antimicrobials, antiemetics, anticholinergics, bronchodilators,antivirals, myorelaxants, cholinergic agents, central nervous systemstimulators, cardioactive agents, beta-adrenergic agonists, hormones,anxiolytics, antidepressants, antipsychotics, opioid antagonists, andcoronary dilators.
 20. A matrix as claimed in claim 19, wherein thenon-steroidal anti-inflammatory is selected from the group consisting ofdiclofenac, fenoprofen, flurbiprofen, ibuprofen, ibuproxam, indoprofen,ketoprofen, ketorolac, naproxen, oxametacine, oxyphenbutazone,piroxicam, suprofen, and celecoxib.